Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family. The EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Gα) subunits and beta-gamma (Gβγ) dimers. Ultimately, this S1P-driven signaling results in cell survival, increased cell migration and, often, mitogenesis. The recent development of agonists targeting S1P receptors has provided insight regarding the role of this signaling system in physiologic homeostasis. For example, the immunomodulator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol), that following phosphorylation, is a pan S1P receptor agonist, revealed that S1P tone influences lymphocyte trafficking (1-4). The utility of an S1P receptor agonist was unexpected indeed, prior speculation focused on the potential (as yet unrealized) for S1P antagonists as anti-angiogenic agents.
Recent findings also suggest a physiological influence for S1P in the vasculature. While not yet explored in detail, it has been hypothesized that S1P may mediate anti-inflammatory actions on endothelial cells through its release from high-density lipoprotein (HDL) (5). Furthermore, an S1P1 receptor antagonist described herein blocked the anti-inflammatory action of S1P, thereby providing evidence that this effect maps to the S1P1 receptor. If verified, this result would expand the role of the S1P1 receptor to include influencing monocyte extravasation and further highlight how the development of S1P-receptor specific compounds is expanding our understanding of the biology of this important signaling system.
To characterize the biology associated with individual S1P receptors further, we have undertaken a program to develop S1P analogs with the twin goals of expanding the structure-activity relationships (SAR) associated with S1P receptor interactions and identifying receptor specific compounds. Our studies have lead to the identification of a series of S1P analogs that behave as antagonists at two of the five S1P receptors.
There is a long felt need in the art for S1P analogs which can modulate activity of more than one of the S1P receptors. The present invention satisfies these needs.